Field of the Invention
The present invention relates to an agent for the treatment and/or prophylaxis of an autoimmune disease, an agent for the formation of regulatory T cells (TReg) in an organism and various methods in which the agents according to the invention are used.
Related Prior Art
Autoimmune diseases are characterized by an excessive reaction of the immune system against endogenous tissue. The immune system erroneously recognizes endogenous tissue as foreign bodies to be combated. This results in severe inflammatory reactions, which lead to damage to organs affected by them.
An important part in distinguishing between endogenous and exogenous structures is played by T lymphocytes or T cells, which are “trained” in the thymus to dock only onto endogenous cell surface molecules, the so-called MHC molecules, and thus to tolerate endogenous structures. These processes are called “clonal deletion” and “clonal selection”. During the initial selection in the thymus, only those T cells, which are able to recognize MHC molecules on the endogenous cell membranes survive, while the binding is however not so strong that it could lead to activation of the T cells. T cells which cannot bind to or recognize endogenous MHC molecules at all are eliminated. In the clonal deletion also taking place in the thymus, those T cells which are able to “unerringly” recognize and strongly bind endogenous MHC molecules in such a manner that they would be activated, which would in the end lead to the destruction of endogenous cells, are eliminated. This process is one of those measures which the immune system takes in order to be able to protect the “self” and combat the “exogenous”.
In autoimmune diseases, a group of the T cells behaves abnormally. In addition to the still functioning defence from exogenous molecules and organisms, they now also attack endogenous structure. Organs or tissues are perceived as exogenous. There can be various consequences: if vital structures are affected, an autoimmune disease will take a fatal course. The immune system directs its defence against these structures, cellular and also humoral defence reactions are set in motion, and autoantibodies are formed, as a result of which the organs affected in the course of time cease to function. Most commonly, the immune system is weakened and the body becomes susceptible to all kinds of diseases. Under some circumstances, recognition of the exogenous is also disrupted, and as a result the spreading of degenerated cancer cells can no longer be effectively prevented, and those affected are more susceptible to infectious diseases. In the course of the disease, cells of the immune system destroy the endogenous structures, while the body's repair mechanisms attempt as far as possible to regenerate the damaged organ parts. As a rule, without treatment this erroneous attack of the defensive system continues throughout life or until the complete destruction of the target structure.
In spite of intensive research, the exact causes of autoimmune diseases are still unclear. Accepted hypotheses are based on the assumption that autoimmune diseases are acquired through a genetic predisposition, e.g., owing to the presence of certain MHC molecule types, in combination with external influences. If such genetically determined factors are present in the body of the person affected, and in addition unfavourable environmental factors such as severe stress, infections, pregnancy, etc., occur, this can lead to the onset of autoimmune diseases.
The immune system consists of various cells which are capable of combating infectious agents which have invaded the body. The mechanism of the immune response includes the activation of specialized cells and the acquisition of effector functions, such as the cytotoxicity of certain T cells, which express the so-called CD8 transmembrane glycoprotein and which are therefore described as CD8+T cells.
Regulatory T cells (TReg), previously also described as suppressor T cells, are a specialized subgroup of the T cells. They have the function of suppressing the activation of the immune system and thereby regulating the self-tolerance of the immune system. As a result, in the healthy organism they prevent the onset of autoimmune diseases. Various TReg populations have been described, including those which express the proteins CD4, CD25 and Foxp3 and are therefore described as CD4+CD25+Foxp3+ T cells. In addition, TReg have been described which do express CD4 and Foxp3, but not CD25, so-called CD4+CD25−Foxp3+ T cells.
Lan et al. (2005), Regulatory T cells: development, function and role in autoimmunity, Autoimmun Rev. 4(6), p. 351 to 363, describe a murine model in which the depletion of CD4+CD25+ regulatory T cells leads to the spontaneous development of autoimmune diseases.
Chatila T. A. (2005), Role of regulatory T cells in human diseases, 116(5), p. 949 to 959, report that a congenital deficiency of CD4+CD25+ regulatory T cells due to a mutation in the gene which codes for the protein Foxp3 contributes to the development of autoimmune diseases.
There is a review concerning regulatory T cells in the journal “Nature Immunology”, which was published in March 2005.
Autoimmune diseases are treated according to the organ affected. In this, the basic principle of the causal therapy is to suppress the activity of the immune system by administration of immunosuppressants, e.g., cortisone. These substances are characterized by multiple systemic side-effects and interactions, owing to which attempts have been made to develop new drugs which specifically influence the mechanisms involved in the disease event. Examples of this are natalizumab and infliximab. Natalizumab is a monoclonal antibody and selective inhibitor of IgG4, an adhesion molecule which is located on the surface of white blood cells. Natalizumab inhibits the migration of white blood cells into inflammation foci and is used for the treatment of particularly aggressive forms of plaque progressive multiple sclerosis. Infliximab is a chimeric monoclonal antibody against tumour necrosis factor α (TNFα), which plays a key part in autoimmune inflammatory reactions. Infliximab is used in rheumatoid arthritis, Crohn's disease, Bechterew disease and psoriasis.
In Ehrenstein et al. (2004), Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy, J. Exp. Med., Vol. 200, No. 3, p. 277-285, it is reported that, as a monoclonal antibody directed against TNFα, infliximab can improve the therapy of rheumatoid arthritis.
A similar suggestion is made by Nadkarni et al. (2007), Anti-TNFα therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β, JEM Vol. 204, p. 33-39.
Bresson et al. (2006) suggest the treatment of type I diabetes by combined administration of an anti-CD3ε specific antibody and a proinsulin peptide.
Vandenbark et al. (2008), Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis, Immunology Vol. 123, p. 66-78, describe an improvement in the control of the autoreactive response in multiple sclerosis after vaccination of the patients with certain TCR peptides.
Although these newer substances act very specifically, severe side-effects can occur, e.g., the onset of progressive multifocal leukoencephalopathy. For this reason, only three months after its first registration in the USA, natalizumab was again withdrawn from the market. The costs of these new active substances are very high. At present, 300 mg of natalizumab costs over 2,000.00 Euros. 200 mg of infliximab costs, ca. 1,700.00 Euros.